Process for the production of 7-aminocephalosporanic acid



United States Patent 3,367,933 PROCESS FOR THE PRODUCTION OF7-AMINOCEPHALOSPORANIC AClD Stephen Eardley, Ruislip, England, MichaelEdgar Hall, Swansea, Wales, and John Francis Oughtou, Gerrards Cross,and Peter John May, North Harrow, England, assignors to GlaxoLaboratories Limited, Greenford, England, a British company No Drawing.Continuation of application Ser. No. 267,928, Mar. 26, 1963. Thisapplication July 19, 1966, Ser. No. 566,387 Claims priority, applicationGreat Britain, Mar. 28, 1962, 11,874/ 62 5 Claims. (Cl. 260243) Thisapplication is a continuation of application Ser. No. 267,928, filedMar, 26, 1963.

This invention is concerned with the production of 7-aminocephalosporanic acid from cephalosporin C and salts thereof.

7-aminocephalosporanic acid (7-ACA) is a product produced by thehydrolysis of cephalosporin C and may be used as an intermediate for theproduction of N-acyl analogues of cephalosporin C.

It is an object of the present invention to provide improved processesfor the production of 7-aminocephalosporanic acid from cephalosporin Cwhich enable the desired compound to be obtained in good yield and highpurity.

According to the invention, therefore, there is provided an improvedprocess for the production of 7-aminocephalosporanic acid fromcephalosporin C or a salt thereof which comprises subjectingcephalosporin C or a salt thereof to the action of nitrosyl chloride ina mixed solvent medium comprising formic acid and an inert diluent, asherein defined, and decomposing the resultant intermediate with acompound containing an active hydrogen atom, e.g. a hydroxylic compound,to form 7- aminocephalosporanic acid.

The expression inert diluent is used herein to define organic solventshaving the following characteristics:

(i) Substantial inertness to nitrosyl chloride and cephalosporin C;

(ii) substantial inability to yield anions in solution in formic acid;and

(iii) substantial inability to discharge carbonium ions.

If the diluent is unable to fulfill the conditions, diminished yieldsmay result as compared with the use of nitrosyl chloride in a liquidmedium consisting of formic acid alone. For example, dimethylformamidemay combine With carbonium ions and this would lead to diminishedyields. On the other hand if the diluent is ableto fulfill theseconditions improved yields as compared with the use of a liquid mediumconsisting of formic acid alone can be obtained.

The relative proportions of the solvents in the mixed solvent mediumwill depend on the nature of the inert diluent, although, in general,proportions of 0.25:1 to 2:1, preferably 0.25:1 to 1.521 (v./v.) ofinert diluent; formic acid may be used. In many cases a ratio of 1:1will be found to be satisfactory. If too much inert diluent is presentit may suppress the ionizing power of the formic acid thus leading to areduced instead of an enhanced yield.

The term inert diluent as used herein comprises various types ofsolvents including hydrocarbons and nitrohydrocarbons. Hydrocarbonswhich may be used include alkanes, egg. in the form of petroleumfractions, and aromatic hydrocarbons e.g. benzene, toluene and thexylenes. Nitrohydrocarbons which may be used include nitroalkanes e.g.nitrornethane, nitroethane, l-nitropropane and 2'nitropropane andnitro-aromatic compounds ice egg. nitrobenzene. Other solvents which maybe used include halogenated hydrocarbons, particularly those whichcontain both hydrogen and halogen atoms e.g. dichloromethane, chloroformand 1,2-dichloroethane and alkyl nitriles e.g. acetonitrile.

Some of the inert diluents, particularly those which are only slightlypolar, are not freely miscible with formic acid. This may not bedisadvantageous, since the inert diluent may extract the nitrosylchloride into its phase and permit a slower and more easily controlledreaction in the other phase. This in turn may prevent excessive reactionwith the nitrosyl chloride. However, in general, we prefer that thediluent should form a single liquid phase with the formic acid.

An important advantage arising from the use of miscible inert diluentsis that it enables the reaction to be effected at a lower temperaturethan would be possible with the use of formic acid alone. Whilst thehydrolytic process according to the invention can be carried out attemperatures up to about 60 C., We prefer to operate at a temperaturebetween -20 and +10 C., particularly between -S and +5 C.

The nitrosyl chloride should preferably be used in excess although thereis no advantage to be gained in using a large excess since this willonly have to be destroyed subsequently. In general we prefer to use1.53.0 molecular equivalents of nitrosyl chloride.

One may use free nitrosyl chloride or nitrosyl chloride prepared in situe.g. from an alkyl nitrite and hydrogen chloride.

A further advantage of the above process is that it can be modified inits operation to avoid or reduce disadvantages inherent in the use offormic acid by itself. Thus the reaction of nitrosyl chloride with asolution of cephalosporin C in formic acid is very vigorous and isaccompanied by much foaming and gas evolution. We have found that thisdisadvantage can be substantially reduced by adding a solution ofnitrosyl chloride in the inert diluent to a solution of cephalosporin. Cin a mixture of formic acid and inert diluent. Alternatively thecephalosporin C may be dissolved in formic acid, the nitrosyl chloridein the inert diluent and the two solutions added simultaneously orintermittently to a mixture of formic acid and inert diluent. Theaddition can be effected over a period of, for example, five minutes andthe reaction mixture allowed to stand for, say, a further ten minuteswithout untoward side reactions occurring. One is therefore enabled notonly to avoid the disadvantages attending a vigorous reaction but alsoto exercise greater control over the reaction. These factors areimportant in large scale manufacture.

If the nitrosyl chloride is prepared in situ it may be necessary todissolve the precursors in diiferent solvents to those which one wouldchoose for pre-prepared nitrosyl chloride. Thus we prefer to dissolvethe latter in inert diluent but, for example, when forming nitrosylchloride from iso-amyl nitrite and hydrogen chloride we prefer todissolve the precursors in the formic acid.

The product obtained after reaction of the nitrosyl chloride withcephalosporin C is an intermediate which can be converted to7-aminocephalosporanic acid by reaction with a compound containing anactive hydrogen atom e.g. water.

However, it has been found that said intermediate, whether obtained bythe process according to the invention or otherwise, can be converted to7-aminocephalo sporanic acid in improved yield and/or increased purityby dissolving the intermediate, either in solution in a dissolved formor in a substantially solvent-free state, in a relatively large volumeof a lower alkanol and then adding a base to precipitate the7-aminocephalosporanic acid.

By proceeding in this maner the desired end product can be obtained as awhite precipitate which can readily be filtered off, washed and dried toyield a product of high yield and purity.

Accordingly, the invention also provides a process for the production of7-aminocephalosporanic acid from the intermediate arising from thereaction of cephalosporin C or a salt thereof with a nitrosating agent,preferably nitrosyl chloride, which comprises decomposing saidintermediate with a lower alkanol and adding a base to precipitate the7-aminocephalosporanic acid from the resultant solution.

Whilst this further process according to the invention can lead to animproved yield of 7-ACA derived from minutes and the solvents thenevaporated on a rotary evaporator with a bath temperature of 50 C. Theresulting gum was dissolved in water ml.) and the solution (pH 1.0) wasadjusted to pH 3.5 by the addition of 7.5 N-ammonia solution. Theprecipitated 7-ACA was allowed to stand at 0 for one hour and was thencollected, washed with water, and dried (925 mg, 40%; A max. 260 III/L;e 7,800).

The reaction was repeated in Examples 26 except that 3 equivalents (1.66g.) (cf. Example 9) of nitrosyl chloride were used and instead ofnitromethane, the following solvents nitroethane, l-nitropropane,2-nitropropane, acetonitrile and dichloromethane were used. The resultsobtained are shown in Table 1.

TABLE 1.REACTIONS IN VARIOUS SOLVENT LHXTURES Solvent; added to Time ofTemper- A max. at Yield of Example formic acid Addition, ature, C.Yield, mg. 260 m 7-ACA,

min. percent Nitrocthane 21. 5 -2 912 7, 534 39 l-nitropropane 11.5 -2841 7, 534 3G Q-nitnopropand. 15. 75 --2. 5 861 7, 371 37 Acetonitrile 96 752 7, 698 32 Dichloromethane 11. 5 -2 S40 7, 942 36 *Solutions ofN001 in 2-nitropropane should be used immediately as reaction betweenthe two appears to occur.

other processes involving the use of nitrosating agents (e.g. the use ofnitrosyl chloride in a liquid medium consisting only of formic acid) itis preferred to employ it in conjunction with the hydrolytic processaccording to the invention involving the use of an inert diluent sinceimproved yields can be obtained which cannot be explained on an additivebasis.

The lower alkanol used is preferably methanol. Whilst ethanol, propanol,etc. can be used, the yields obtained are not in general so good asthose obtained with methanol which is the alkanol of choice.

The lower alkanol is preferably used in an amount of from 12 ml. to 130ml. per gram of cephalosporin C starting material calculated as thesodium salt dihydrate. Advantageously one uses 60-75 ml. of loweralkanol per gram of cephalosporin C on the stated basis.

The isoelectric point of 7-aminocephalosporanic acid in water is circa3.5 and whilst pHs above or below this figure may be used, we find thatoptimal results are obtained in methanol by adjusting the pH with thebase to circa 3.5. A preferred pH range is 2.5 to 4.5. pHs referred toin connection with isoelectric point are as measured directly on thesolution using a glass electrode.

The base used to precipitate the 7-ACA is conveniently a concentratedsolution of ammonia in a solvent such as water or methanol. The 7-ACAcan be recovered from the alkanolic solution using very little ammoniaand consequently little ammonium formate is formed. We have found thatconcentrated solutions of ammonium formate increase the solubility of7-ACA in water and hence, as compared with recovery of 7-ACA from anaqueous solvent medium, one is able to obtain increased yields by theprocess according to the invention by avoiding losses due tosolubilization of 7-ACA.

The 7-ACA obtained by the use of a lower alkanol followed by addition ofa base is washed and dried. It may be used without further purificationfor conversion into other compounds.

In order that the invention may be well understood the followingexamples are given by way of illustration only. Unless otherwise statedmeasurements of ultraviolet absorption were made on solutions in 0.01N-hydrochloric acid.

Example 1 Solutions of cephalosporin C sodium salt, dihydrate (4 g.) in98% formic acid ml.) and nitrosyl chloride (1.11 g.; 2 equivalents) innitl'omcthane (25 ml.) were run at -3 with stirring, into a vessel overa period of 9.5 minutes. The mixture was stirred for a further 2 Example7 Solutions of cephalosporin C sodium salt, dihydrate (4 g.) in 98%formic acid (25 ml.) and nitrosyl chloride (1.66 g.; 3 equivalents) inbenzene (25 ml.) were mixed with stirring (see Example 1) over a periodof 12 minutes at 10. The mixture was stirred for a further 2 minutesthen allowed to separate into two phases. The lower phase was evaporatedon a rotary evaporator with a bath temperature 50. The resulting gum wasdissolved in water (20 ml.) and the solution (pH 0.9) was adjusted to pH3.5 by the addition of 7.5 N-ammonia solution. The precipitated 7-ACAwas allowed to stand at 0 for 1 hour and was then collected, washed withwater, and dried (765 mg, 33%; A max. 260 mg, 6 7,500).

Example 8 A solution of cephalosporin C sodium salt, dihydrate (4 g.) in98% formic acid (25 ml.) and nitromethane (25 ml.) and another ofnitrosyl chloride 1.66 g. 3 equivaents) in petroleum-ether (B.P. 40-60")(25 ml.) were run together with stirring into a vessel over a period of24 minutes at -7 (see Example 1). The mixture was stirred for a further2 minutes, and allowed to separate into two phases. The lower phase wasevaporated on a rotary evaporator with a bath temperature of 50. Theresulting gum was dissolved in water (20 ml.) and the solution (pH 0.95)was adjusted to pH 3.5 by the addition of 7.5 N-ammonia solution. Theprecipitated 7-ACA was allowed to stand at 0 for 1 hour and was thencollected, washed with water, and dried (917 mg; 39%; A max. 260 m e8,000).

Example 9 Solutions of cephalosporin C sodium salt, dihydrate (4 g.) in98% formic acid (25 ml.) and nitrosyl chloride (1.66 g.; 3 equivalents)in nitromethane (25 ml.) were added to a mixture of formic acid (15 ml.)and nitromethane (35 ml.) with stirring over a period of 12.5 minutes at2 (see Example 1). The mixture was stirred for a further 2 minutes andthe solvents then evaporated on a rotary evaporator with a bathtemperature of 50. The resulting gum was dissolved in water (20 ml.) andthe solution (pH 1.2) was adjusted to pH 3.5 by the addition of 7.5N-ammonia solution. The recipitated 7-ACA was allowed to stand at t forone hour, and was then collected, washed with water, and dried (882 mg,37%; A max. 260 m 6 8,050).

Example A solution of .cephalosporin C sodium salt, dihydrate (5 g.) informic acid (98-100% 120 ml.) was stirred and cooled to +3 in a coolingbath at -10. Nitrosyl chloride (1.75 ml.) was added dropwise from arefrigerated dropping funnel over a period of two minutes, during whichtime the temperature rose to 26 and there was a copious evolution ofgas. After the mixture had been stirred for a total of five minutes itwas poured into dry methanol (100 ml.) and the pH of the solutionadjusted to 3.6 with 7.5 N-ammoniu'm hydroxide, when7-'aminocephalosporanic acid precipitated. After being cooled themixture was filtered and the white solid washed with methanol. The yieldof 7-ACA was 1.03 g. (34%, A max. 260 mp, e 8000).

Example 11 A solution of cephalosporin C sodium salt, dihydrate (5 g.)in formic acid (98-100%; ml.) was cooled to +3 in a cooling bath at '10and stirred whilst nitrosyl chloride (1.75 ml.) was added dropwise froma refrigerated dropping funnel over a period of two minutes. After atotal time of five minutes the solution was rapidly evaporated on arotary evaporator and the residual gum dissolved in dry methanol 100ml.). Addition of 7.5 N- ammonium hydroxide to pH 3. 6 causedprecipitation of 7-ACA (1.16 g.; 40%, A max. 260 m e 7700).

Example 12 Treatment of ce'phalosporin C sodium salt, dihydr-a'te (5 g.)with nitrosyl chloride and evaporation of the reaction mixture exactlyas in Example 11 gave a gum, which was dissolved in dry methanol (50ml.). Adjustment of the pH of this solution to 3.6 with methanolicammonia gave 7-ACA (1.3 g., 45%), A max. 260 ma (6 7,700).

Example 13 Cephalos'porin C, sodium salt, dihydrate (30 g., 91.0%purity) was dissolved in formic acid (188 ml., 98100%) and nitromethane(1-25 ml.) added to this with stirring. The stirred reaction mixture wascooled to --5 and a solution of nitrosyl chloride (7 ml.) innitromethane (63 ml.) added dropwise over 6 mins. The temperature duringthe reaction was kept between -5 and 0. After the addition of thenitrosyl chloride solution, the reaction mixture was stirred for afurther 14 mins. at the same temperature and then poured into methanol(3 litres) with stirring. After 10 mins. this solution was adjusted topH 3.5 with ammonium hydroxide solution (s.-g. 0.88) and the precipitatefiltered off. This was washed with methanol (3X30 ml.) and then withether (3X30 ml.) and finally dried at 40 under vacuum. Yield 9.92 g.(63.2% theory).

This compound travels as a single spot on electrophoresis at pH 1.9 inan identical manner to 7-ACA, and gives an identical ninhydrin colourreaction to this authentic specimen. U.V. A max. 260 m e 8440.

Example 14 Example 13 was repeated but "the reaction mixture was pouredinto ethanol (I.M.S.) instead of methanol, the yield obtained in thiscase being 56.8%, A max. 260 m e 7300.

Example 15 Example 13 was repeated but the mixture poured inton-propanol instead of methanol. The yield was 44.3%, A max. 260 m 66,890.

Example 16 Cephalosporin C sodium salt, dihydrate (24 g., 91.0% purity)was dissolved in formic acid (50 ml., 98100%) and the solution cooled to0 C. Then nitrosyl chloride (5.4 ml.) was dissolved in acetonitrile (50ml.) at 10 C. These two solutions were added to a stirred mixture offormic acid (70 ml.) and acetonitrile (70 ml.)

at equal rates over 13 mins., the reaction mixture being kept between -5and +5 C.

After stirring for a further 5 mins. the reaction mixture was pouredinto methanol (2 litres) and the solution adjusted to pH 3.5 withammonium hydroxide solution (s.g. 0. 88). The precipitate was filteredoff and washed with methanol (2x75 ml.), ether (2X50 ml.) and finallydried under vacuum overnight at room temperature. Yield of 7-ACA 6.67 g.(54%) U.V. A max. 259 mu, :2 7,896.

Example 17 Cephalosporin C sodium salt, dihydrate (30 g., 91% purity)was dissolved in cold formic acid (94 ml), diluted with dichloro-methane(63 ml.) and stirred at 3 while a solution of nitrosyl chloride (7 ml.)in dichloromethane (3 1 ml.) was added dropwise during 5 minutes. Aftera further 5 minutes the reaction solution was poured into methanol (2litres) and the pale yellow solution was titrated to pH 3.5 withammonium hydroxide solution (sag. 0.88). The resultant suspension wascooled to 10, the precipitate was collected by filtration, washed withmethanol (100 ml.) and diethyl ether (100 ml.) and dried in vacuo at 40to give a 54.3% yield (8.55 g.) o 7-AOA U.V. A max. 259 m 6 8,090.

Example 18 *Cephalosporin C sodium salt, dihydrate (88% purity, 30.0 g.)in formic acid (188 ml., water content 0.8%) and dichloremethane (158ml.) was stirred at 3 with a slow stream of nitrogen passing through theliquid. The solution was treated with a cooled solution of nitrosylchloride (7.0 ml.) in dichloro-methane (30 ml.) over 8 minutes at 0 to-3. The reaction mixture was stirred for a further 8 minutes at 0 andthen poured into methanol (2 1.). The pH of the clear solution wasadjusted to 3.5 with ammonium hydroxide solution (12.0 ml; s.g. 0.88)and the mixture cooled down to 10' during 40 minutes. The precipitatewas filtered oil and washed with methanol m1.) and then with ether (60ml.) by displacement. The pale cream solid was dried at 40 in vacuo togive 7-ACA (8.81 g., 58%), A max. 260 m 6 7,490.

Example 19 Solutions of cephalosporin C sodium salt, dihydra-te (4 g.)in 9'8%-.formic acid (25 ml.) and nitrosyl chloride (1.66 g., 3 equivs.)in nitrobenzene 25 ml.) were mixed with stirring over a period of 9mins. at 1 to 4. The mixture was stirred for a further 2 mins. and theformic acid was then evaporated on a rotary evaporator with a bathtemperature of 50 over a period of 7 mins. The nitrobenzene was decantedfrom the residual gum which was dissolved in water (2 5 ml.). Thissolution was then shaken with the nitro benzene layer and separated. Thentitrobenzene was washed with more water (5 ml.) and the combinedaqueous solutions (.pH 1.1) were adjusted to pH 3.5 by addition of 7.5N-ammonia solution. 7-ACA precipitated as an orange solid and wasallowed to stand at 0 tor one hour before being collected, washed withwater and dried (909 mg, 39.5%), A max. 260 m (e 7,780).

Example 20 Cephalosporin C potassium salt (73% purity, 7.38 g.) wasadded to formic acid (45 ml., water content 0.5%) and dichlorornethane(15 ml.) at 0 to 2. Dichloromethane (21 ml.) was added. Iso-amyl nitrite(4.82 g.) was added to a cooled solution of dry hydrogen chloride (0.86g.) in formic acid (24.6 ml.) which was then added over 10 minutes tothe cephalosporin C solution at 0 to 5". The reaction mixture wasstirred for a further 10 minutes, the temperature rising to 3, and waspoured into methanol (468 ml.) at 4. After stirring for a further 30minutes, the pH was adjusted to 3.4 with ammonium hydroxide solution(12.5 ml., s.g. 0.88) and the mixture was stirred for 3 hours at -4. Theprecipitate was filtered off and washed with chilled methanol (27 7 ml.)and ether (9 ml.). The buff coloured solid was dried at 40 in vacuo togive 7-ACA (1.64 g., 51%), A max. 260 III/1., E 7,690.

Example 21 A stirred mixture of formic acid (375 ml., 98%) and methylenechloride (300 ml.) was cooled to 5 Cephalosporin C calcium salt (60 g.)was added and the mixture stirred for 10 minutes. Nitrosyl chloride (14ml.) in methylene chloride (75 ml.) was added to the stirred mixtureover 8 minutes while the temperature was kept between 2 and The mixturewas kept at this temperature for a further 8 minutes, then poured intomethanol (2.5 litres). After the mixture had been standing for minutes,the pH was adjusted to 3.5 with ammonium hydroxide solution (s.g.0.880). The mixture was allowed to stand in the refrigerator for onehour. It was then filtered, the precipitate washed with methanol (2X50ml.) and ether (2X50 ml.) and dried under vacuum to give7-aminocephalosporanic acid (41.2%),

)\ max. 263 my, E1"; 273 (pH 7 phosphate bufier) Example 22 A stirredmixture of formic acid (375 ml., 98%) and methylene chloride (300 ml.)was cooled to -5. Cephalosporin C potassium salt (60 g.) was added andthe mixture stirred for minutes. Nitrosyl chloride (14 ml.) in methylenechloride (75 ml.) was added to the stirred mixture over 8 minutes whilethe temperature was kept between 2 and 0. The mixture was kept at thistemperature for a further 8 minutes, then poured into methanol (2.5litres). After the mixture had been standing for 5 minutes, the pH wasadjusted to 3.5 with ammonium hydroxide solution (s.g. 0.880). Themixture was allowed to stand in the refrigerator for one hour. It wasthen filtered, the precipitate washed with methanol (2X50 ml.) and ether(2X50 ml.) and dried under vacuum to give 7-a'minocephalosporanic acid(52.2%),

A max. 263 m Ei'f'g 283 (pH 7 phosphate buffer) Example 23 A stirredsolution of formic acid (63 ml., 98%) and methylene chloride (43 ml.)was cooled to 3. Cephalosporin C (free acid) (10 g.) was added and themixture stirred for 10 minutes. Nitrosyl chloride (2.4 ml.) in methylenechloride (20 ml.) was added to the stirred mixture over 7 minutes andthe mixture stirred for a further 8 minutes at between 0 and 2. Themixture was then poured into methanol (667 ml.). After the mixture hadbeen standing for 5 minutes the pH was adjusted to 3.5 with ammoniumhydroxide solution (s.g. 0.880). The mixture was allowed to stand at 0for one hour. It was then filtered, the precipitate washed with methanoland ether and dried under vacuum to give 7-aminocephalosporanic acid(45.7%),

A max. 260 me, Ei im. 296

We claim:

1. In a process for the production of 7-aminocephalosporanic acidwherein a cephalosporin compound selected from the group consisting ofcephalosporin C and a salt thereof is reacted with nitrosyl chloride ina solvent medium at a temperature of not more than C. the resultingintermediate is decomposed with a compound containing an active hydrogenatom and said 7-aminocephalosporanic acid is precipitated by addition ofa base, the steps of carrying out the reaction with nitrosyl chloride ina mixed solvent medium comprising formic acid and an inert diluentselected from the group consisting of a nitroloweralkane, nitrobenzene,a haloloweralkane containing both hydrogen and halogen atoms and aloweralkyl nitrile, and contacting the resulting intermediate withmethanol prior to adding said base.

2. A process as claimed in claim 1 in which said inert diluent isnitromethane.

3. A process as claimed in claim 1 in which said inert diluent ismethylene chloride.

4. A process as claimed in claim 1 in which said inert diluent isacetonitrile.

5. A process as claimed in claim 1 in which said intermediate is in asubstantially solvent-free state prior to contact with methanol.

References Cited UNITED STATES PATENTS 3,188,311 6/1965 Morin et al.260243 NICHOLAS S. RIZZO, Primary Examiner.

1. IN A PROCESS FOR THE PRODUCTION OF 7-AMINOCEPHALOSPORANIC ACIDWHEREIN A CEPHALOSPORIN COMPOUND SELECTED FROM THE GROUP CONSISTING OFCEPHALOSPORING C AND A SALT THEREOF IS REACTED WITH NITROSYL CHLORIDE INA SOLVENT MEDIUM AT A TEMPERATURE OF NOT MORE THAN 60*C. THE RESULTINGINTERMEDIATE IS DECOMPOSED WITH A COMPOUND CONTAINING AN ACTIVE HYDROGENATOMS AN D SAID 7-AMINOCEPHALOSPORANIC ACID IS PRECIPITATED BY ADDITIONOF A BASE, THE STEPS OF CARRYING OUT THE REACTION WITH NITROSYL CHLORIDEIN A MIXED SOLVENT MEDIUM COMPRISING FORMIC ACID AND AN INERT DILUENTSELECTED FROM THE GROUP CONSISTING OF A NITROLOWERALKANE, NITROBENZENE,A HALOLOWERALKANE CONTAINING BOTH HYDROGEN AND HALOGEN ATOMS AND ALOWERALKYL NITRILE, AND CONTACTING THE RESULTING INTERMEDIATE WITHMETHANOL PRIOR TO ADDING SAID BASE.